Nova1 is a master regulator of alternative splicing in pancreatic beta cells

Nucleic Acids Res. 2014 Oct;42(18):11818-30. doi: 10.1093/nar/gku861. Epub 2014 Sep 23.

Abstract

Alternative splicing (AS) is a fundamental mechanism for the regulation of gene expression. It affects more than 90% of human genes but its role in the regulation of pancreatic beta cells, the producers of insulin, remains unknown. Our recently published data indicated that the 'neuron-specific' Nova1 splicing factor is expressed in pancreatic beta cells. We have presently coupled specific knockdown (KD) of Nova1 with RNA-sequencing to determine all splice variants and downstream pathways regulated by this protein in beta cells. Nova1 KD altered the splicing of nearly 5000 transcripts. Pathway analysis indicated that these genes are involved in exocytosis, apoptosis, insulin receptor signaling, splicing and transcription. In line with these findings, Nova1 silencing inhibited insulin secretion and induced apoptosis basally and after cytokine treatment in rodent and human beta cells. These observations identify a novel layer of regulation of beta cell function, namely AS controlled by key splicing regulators such as Nova1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Apoptosis
  • Calcium / metabolism
  • Cytokines / pharmacology
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Nerve Tissue Proteins / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology*
  • Rats, Wistar
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism

Substances

  • Cytokines
  • FOXO3 protein, rat
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Insulin
  • NOVA1 protein, human
  • Nerve Tissue Proteins
  • Nova1 protein, rat
  • RNA-Binding Proteins
  • Foxo1 protein, rat
  • Receptor, Insulin
  • Calcium